Though inhibition of multiple HIV proteins is therapeutically viable, HIV reverse transcriptase (RT) has been the key target.1 Nucleoside RT inhibitors (NRTIs) including AZT are incorporated into the product DNA causing premature strand termination, while the non-nucleoside RT inhibitors (NNRTIs) bind to an allosteric site ca. 10-Å away from the polymerase active site.2 The present inventors' efforts at discovery of new NNRTIs are intended to address continuing issues concerning the possible emergence of new viral strains, improved dosing, long-term tolerability, and safety.3 Numerous compounds in multiple series have been prepared that are both potent against the wild-type (WT) virus and that have auspicious computed pharmacological properties.4,5 Improvement in the performance of these compounds against clinically relevant viral variants is still desired. To address resistance from the outset, docking was done on multiple RT structures to seek consensus high-scoring hits. More than two million compounds from the ZINC library were screened with Glide using a conventional WT structure (1rt4), one with an alternative “down” conformation for Tyr181 (2be2), and a structure that incorporated the troublesome Tyr181Cys mutation (1jla).6 Though only nine compounds were purchased, three showed 5-12 μM activity against one or both viral strains in infected T-cell assays.
As described here, among the three actives, we have most pursued lead-optimization for compound 1, which showed 4.8 μM potency towards WT HIV-1.6 1 bears some structural similarity to the ligands, TNK-651 (2) and R221239 (3), from the 1 jla and 2be2 crystal structures, respectively.7,8 Their roots can be traced back further to thymine analogs in the HEPT class including emivirine (MKC-442, 4), which progressed to phase III clinical trials.9 Various attributes of 1 are appealing including that it is a diphenylmethane derivative with a novel terminal uracil group, it likely has diminished metabolic liabilities compared to 3 and better computed aqueous solubility according to QikProp,10 and refinement of substituents in the phenyl rings can be expected to be productive. Thus, optimization of 1 was initiated using a computationally driven approach, primarily guided by results of free-energy perturbation (FEP) calculations for complexes of the inhibitors with HIV-RT.4
